Almost one in ten people experience appendicitis, a disease in which a small part of the intestine called the appendix becomes inflamed and painful. The usual treatment is hospitalization and general anesthesia and surgery to remove the appendix. It takes people about two weeks to recover. The cause of appendicitis is not entirely clear. One explanation is that the appendix becomes obstructed leading to distention and irreversible lack of blood flow, thus requiring surgical removal to cure. Another explanation is that appendicitis is due to infection, and this suggests that antibiotics may also be effective. Previous non-U.S. studies indicate that many patients can be treated with antibiotics instead of appendectomy, with as many as 70% avoiding surgery and generally experiencing less pain and faster recovery. However, because these studies involved too few patients and did not use ideal methods, doctors do not currently offer this option. Our overall goal is to conduct the first large U.S. trial to determine if antibiotic therapy is a safe and effective alternative to surgery. Our primary aim is to demonstrate that antibiotic treatment produces patient outcomes that are no worse than appendectomy. This aim will be accomplished by conducting a large trial in which patients with appendicitis are assigned by chance to get antibiotics or surgery and testing the hypothesis that those treated initially with antibiotics will experience no more major complications at 30 days than those treated with appendectomy. Secondary aims will be to compare these and other patient-centered outcomes, like duration of pain and time to return to normal activities, over a two-year period. We will also conduct studies to further explore the cause of appendicitis including looking at patient genes to determine who is at risk of the disease, examining the microbiology of appendicitis tissue, and testing blood chemicals, called biomarkers, that may help determine which patients are most likely to respond to antibiotics. Prior to the full- scale trial, we propose a pilot investigation of 30 subjects to demonstrate the feasibility of conducting the full- scale trial. This will be a pivotal clinical trial that will inrease patient choice and provide a safe option for the underserved who do not have ready access to surgical care, while generally enhancing patient health, satisfaction, and productivity, and advancing our scientific understanding of the disease.